Lansoprazole I is an orally active, potent,
irreversible inhibitor of H+,K+-ATPase. It is commercially available in the form of Prevacid® delayed release capsules from TAP Pharmaceuticals Inc. The compound is one of the class of compounds known as gastric “proton pump” inhibitors. These compounds are weak organic bases which diffuse passively from the plasma into the acid-containing intracellular canaliculi of gastric parietal cells. At the low pH found in the lumen of these canaliculi, the protonated compounds rearrange to form pyridinium sulfenamides, which react with sulfhydryl groups present on the ATPase localized in the membranes lining the intracellular canaliculi. The alkylation of the sulfhydryl inhibits the ability of the enzyme to catalyze the secretion of H+ into the lumen in exchange for K+ ions. This inhibition results in an overall reduction in hydrochloric acid secretion by the parietal cells into the cavity of the stomach, thus increasing intragastric pH. As a consequence of reduced acidity in the stomach, the activity of the proteolytic enzyme pepsin is also markedly decreased. Because the proton pump is the final step in acid production and the compounds of this class combine covalently with the associated H+,K+-ATPase, a profound and prolonged inhibition of gastric acid secretion can be achieved.
Proton pump inhibitors have also been reported as useful in treating psoriasis. [See PCT application WO95/18612] The Cmax of racemic lansoprazole is at about 1.5 to 3.5 hours in humans after administration of enteric-coated granules, and the serum half-life is about 1 to 3 hours, although this is variable, depending on the subject=s age and liver function, as discussed below. The major metabolites in human serum are 5-hydroxylansoprazole II (referred to as hydroxylansoprazole herein) and lansoprazole sulfone III.

The two major primary metabolites, lansoprazole sulfone and 5-hydroxylansoprazole, are formed by cytochromes P450 3A (CYP3A) and 2C19 (CYP2C19), respectively. Both metabolites undergo further metabolism to the common metabolite 5-hydroxylansoprazole sulfone via CYP2C19 and CYP3A, respectively. Thus, both CYP enzymes are sequentially—but alternatively—involved in lansoprazole metabolism. CYP2C19, the S-mephenytoin hydroxylase, is polymorphically expressed in the human population. The mutant allele constitutes the recessive trait. Homozygous carriers of the mutation completely lack CYP2C19 and are referred to as poor metabolizers (PM's); persons homozygous and heterozygous for the “normal” allele are extensive metabolizers (EM's). A hereditary deficiency of the alternative enzyme, CYP3A, has not been demonstrated in the human population.
It would be desirable to find a compound with the advantages of lansoprazole which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interactions.